Prolonged use of nitroglycerin may increase severity of subsequent heart attacks

Prolonged use of nitroglycerin may increase severity of subsequent heart attacks

A standard treatment for heart attack patients, nitroglycerin is typically prescribed to aid in opening vessels so blood can flow to the heart more easily. A typical regimen is for hospitalized heart attack patients to be cycled on and off the nitroglycerin, 16 hours on and 8 hours off, to reduce desensitization to the drug.

But a Stanford study published today in Science Translational Medicine shows that prolonged use of the heart medication may actually increase the severity of subsequent heart attacks – and serves as a cautionary tale to cardiologists. In the study, researchers tested the effect of sustained nitroglycerin treatment on the severity of heart attacks using a rat model. As described in our release:

They found that nitroglycerin increased heart attack severity in rats. After 16 hours of nitroglycerin treatment, the heart damage was twice as large as in untreated control animals. Five to eight animals made up each group.

Cardiac function was also significantly diminished in relation to the control animals, as determined by echocardiograms immediately after the heart attack and again two weeks later. And when the rats were given the enzyme activator Alda-1 along with nitroglycerin, the detrimental effects of prolonged nitroglycerin treatment were nearly erased.

John Cooke, MD, PhD, a Stanford professor of cardiovascular medicine who was not involved in the study but has discussed it with the researchers, also provided comment in the release:

Continuous administration of nitroglycerin by patch or by intravenous infusion, as in the coronary care unit, is initially useful in relieving pain and also favorably influences hemodynamics — reduces blood pressure, improves coronary blood flow. However, extended use of this form of nitroglycerin is known to induce tolerance to its own beneficial actions within 12 to 24 hours.

[This study] raises additional concern about the extended use of long-acting or continuous administration of nitroglycerin in the coronary care unit. It is probably best to use nitroglycerin continuously for only short periods of time, and replace the continuous infusion or patch with other medications to reduce symptoms and favorably influence hemodynamics.

Dr. Cooke is Professor of Medicine and Associate Director (Education and Training)of the Stanford Cardiovascular Institute. His research group performs translational work in vascular regeneration from molecule to man. The goal is to transfer basic research insights into clinical trials using a vertically integrated approach with an array of biochemical and molecular tools, cellular and animal models, and clinical research techniques. Our mission is to to build new blood vessels, reverse vascular senescence, and to improve vascular health.

The basic research is focused on induced pluripotential stem cells (iPSCs) for vascular regeneration. We are developing cell-permeant proteins and new chemical entities for nuclear reprogramming, and for differentiation of iPSCs into endothelial cells. Human iPSC-derived endothelial cells are currently being tested in our murine model of PAD. Studies underway include genetic, epigenetic, mitochondrial, and functional characterization of human iPSCs derived from viral versus protein-based strategies. We anticipate that cell permeant peptides will avoid the concerns raised by DNA-based approaches (eg. integration of foreign DNA into the host chromosome), and will provide more control over dosing and duration of action of the reprogramming factors. We are also interested to discover new determinants of endothelial lineage that may enhance the yield of ECs derived from iPSCs. It will be important to determine if iPSC-derived ECs from patients with PAD have normal function, and can incorporate into the host microvasculature and enhance perfusion. Ultimately, we intend to develop clinical grade iPSC-ECs for vascular therapy, and to conduct the first trials of iPSC-EC in patients with PAD.

We have a long-standing interest in two different pathways regulating endothelial function. Endothelium derived nitric oxide synthase(NOS) plays a critical role in EC survival, proliferation, and angiogenesis. There is an endogenous competitive inhibitor of the NO synthase pathway called ADMA (asymmetric dimethylarginine). We find that this molecule is elevated in disorders associated with endothelial dysfunction, and plays a significant role in causing vascular disease. ADMA becomes elevated in people with hypercholesterolemia, diabetes, and other vascular disorders. We find that oxidative stress impairs the activity of the enzyme (DDAH) that degrades ADMA. ADMA accumulates and blocks NO synthesis. Overexpression of DDAH (in our transgenic mouse or in endothelial cell culture) can reduce ADMA levels and increase NO synthesis, with significant consequences on vascular homeostasis and angiogenesis(Jacobi et al Circulation 2005).

More recently we have serendipitously discovered a new pathway modulating angiogenesis (Heeschen et al, Nature Medicine 2001). Nicotinic acetylcholine receptors on endothelial cells are upregulated with hypoxia, and when stimulated (by the endogenous transmitter acetylcholine), these receptors mediate endothelial tube formation in vitro, and angiogenesis in vivo. Of great interest, this pathway is hijacked by nicotine. Thus nicotine can pathologically activate tumor angiogenesis and tumor growth. Nicotine can also stimulate the neovascularization of atherosclerotic plaque, leading to its further growth. These findings suggest a new paradigm for tobacco-related diseases, and provide for a new platform for therapeutic manipulations of the pathway.

Our clinical research is focused on patients with peripheral arterial disease (PAD). We are testing new therapies for angiogenesis and vascular regeneration including novel small molecules and cell therapy. The usual endpoints of our trials are functional capacity (eg. peak walking time), relief of ischemic pain or wound healing. Ongoing trials include gene and cell therapy for enhancing angiogenesis; as well as small molecules for increasing oxygen diffusion, or enhancing skeletal muscle contraction

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